Myotrophin is a soluble 12 kilodalton protein isolated from hypertrophied hearts of spontaneously hypertensive rats and dilated cardiomyopathic human hearts. Myotrophin, when added to neonatal rat myocytes maintained in culture, accelerates myocardial cell growth and increases the number of sarcomeres and gap junction formation. Sen et al., J. Biol. Chem. 1990, 265:16635-16643.
The myotrophin gene is expressed in various rat tissues. Sivasubramanian et al., J. Biol. Chem. 1996, 271(5):2812-2816. Transcripts were found to be most abundant in brain and least in skeletal muscle compared to other tissues. Based upon its ubiquitous nature, it has been suggested that the myotrophin proteins may have an important role in the basic functions of various tissues. Sivasubramanian et al., J. Biol. Chem. 1996,271(5):2812-2816.
Analysis of the primary structure of the rat myotrophin protein has revealed a homology between one of the ankyrin repeats of myotrophin and the I.kappa.B.alpha./rel ankyrin repeats. Sivasubramanian et al., J. Biol. Chem. 1996, 271(5):2812-2816. Putative consensus phosphorylation sites have been identified for protein kinase C and casein kinase II in myotrophin protein, which were also observed in I.kappa.B.alpha. proteins. The significance of these homologies was confirmed in vitro by gel shift assays which showed that recombinant myotrophin has the ability to interact with NF-.kappa.B/rel proteins. Sivasubramanian et al., J. Biol. Chem. 1996, 271(5):2812-2816.
NF-.kappa.B/rel proteins have been shown to be involved in the rapid induction of genes whose products are important in immune responses, inflammation and cell proliferation. NF-.kappa.B is rapidly translocated from the cytoplasm to the nucleus in response to extracellular signals. It is believed that myotrophin is a component of this rapid response system and may be involved in the regulation of expression of hypertrophy-specific genes in the myocardium and I other tissues.
Clearly there is a need for identification and characterization of the human myotrophin gene, the modulation of which may play a role in preventing, ameliorating or correcting dysfunctions or diseases relating to cellular hypertrophy.